Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0022568 (keratitis)
5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 7 days after HSV-1 corneal infection, BALB/c mice develop tissue-destructive inflammation in the cornea termed herpes stromal keratitis (HSK), as well as periocular skin lesions that are characterized by vesicles, edema, and fur loss. CD4(+) T cells and Th1 cytokines contribute to both the immunopathology in the cornea and the eradication of viral replication in the skin. We demonstrate that disruption of CD40/CD154 signaling does not impact the initial expansion of CD4(+) T cells in the draining lymph nodes, but dramatically reduces the persistence and Th1 polarization of these cells. Despite the reduced Th1 response, CD154(-/-) mice developed HSK and periocular skin disease with similar kinetics and severity (as assessed by clinical examination) as wild-type (WT) mice. However, when the composition of the inflammatory infiltrate was examined by flow cytometric analysis, CD154(-/-) mice exhibited significantly fewer CD4(+) and CD8(+) T cells and neutrophils than WT mice at the peak of HSK. Moreover, CD4(+) T cells from infected corneas of CD154(-/-) mice produced significantly less IFN-gamma than those of WT mice when stimulated with viral Ags in vitro. The IFN-gamma production of cells from infected corneas of WT mice was not affected by addition of anti-CD154 mAb to the stimulation cultures. This suggests that CD154 signaling is required at the inductive phase, but not at the effector phase, of the Th1 response within the infected cornea. We conclude that local disruption of CD40/CD154 signaling is not likely to be a useful therapy for HSK.
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PMID:CD154 signaling regulates the Th1 response to herpes simplex virus-1 and inflammation in infected corneas. 1524 Jul 15

Pseudomonas aeruginosa keratitis is one of the most destructive diseases of the cornea. The host response to this infection is critical to the outcome, and is regulated by cytokines produced in the ocular tissue. In this study, we assessed the relative contribution of the cytokines produced in the cornea to the inflammatory response of the whole eye to gain a better understanding of the inflammatory and regulatory processes in the ocular environment during localized corneal infection. C57BL/6 mice were challenged by topical application of P. aeruginosa to wounded corneas. Corneas and whole eyes were harvested 24 h post-challenge and bacterial numbers, myeloperoxidase levels and the levels of cytokines known to be important in keratitis were determined. The site of production of IL-6 and KC in the retina was determined by in situ hybridization. Before infection, 90% of macrophage inflammatory protein (MIP)-2 and approximately 80% of all IFN-gamma and IL-10 produced constitutively in the eye was found outside the cornea. Twenty-four hours after infection, bacterial numbers, levels of myeloperoxidase, and levels of MIP-2 and IL-1 were not different, whether measured in cornea or whole eye. However, expression of IL-6, KC, IFN-gamma and IL-10 was significantly greater in whole eyes than in the corneas of infected eyes. The cells expressing IL-6 and KC in the retina were identified by in situ hybridization. This study indicates that during corneal inflammation, the response of the whole eye as well as the cornea needs to be considered.
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PMID:Contribution of the cornea to cytokine levels in the whole eye induced during the early phase of Pseudomonas aeruginosa challenge. 1587 9

Pseudomonas aeruginosa is a common organism associated with bacterial keratitis primarily resulting from contact lens usage. Advances in our understanding of host innate and adaptive immune responses to experimental infection have been achieved using animal models, including inbred mouse models that are classed as resistant (cornea heals) vs. susceptible (cornea perforates). Evidence has shown that sustained IL-12-driven IFN-gamma production in dominant Th1 responder strains such as C57BL/6 (B6) contributes to corneal destruction and perforation. In contrast, in Th2-responder BALB/c mice, IL-18-driven IFN-gamma production regulates bacterial killing with less corneal destruction. IL-1 and chemotactic cytokines (e.g., MIP-2) recruit PMN to the cornea. The critical role of these cells in the innate immune response and their regulation after bacterial infection has been established. The studies provide a better understanding of the regulatory mechanisms that operate in the cornea after P. aeruginosa challenge, determining susceptibility vs. resistance to disease, and are consistent with long-term goals of providing targets for better treatment of disease.
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PMID:Role of innate and adaptive immunity in the pathogenesis of keratitis. 1601 72

Fumaric acid derivates have been shown to stimulate T helper-2-cytokines (interleukin (IL)-4, -5) without affecting the T-helper-1-cytokine (IL-2, interferon (IFN)-gamma)-response. Herein, the influence of systemic treatment with the fumaric acid derivate dimethylfumarate (DMF) on the secretion of T helper-cytokines and the development of HSV-1 stromal keratitis (HSK) was studied in mice. The corneas from BALB/c mice were infected with 10(5) PFU of HSV-1 (KOS strain). While one group of mice was treated intraperitoneally with PBS, another group of mice received DMF at 15 mg/kg of body weight. Expression of IL-2, -4, -10 and IFN-gamma was analysed in HSV-1 activated lymphocytes by ELISA. The severity of epithelial and stromal herpetic keratitis was investigated clinically. Corneas were studied for the inflammatory cell infiltration, and the CD3-, CD4- and CD8-positive cells were analysed by immunohistochemistry. The IL-2, -4, 10 and IFN-gamma content was measured in the corneas. Virus replication in the eyes was analysed by a plaque-assay. The DTH-response, the HSV-specific T cell proliferation and the serum neutralizing antibody-titres were investigated. DMF increased IL-4 and IL-10, but not IL-2 and IFN-gamma, secretion in activated lymphocytes from the spleen. Incidence and severity of stromal HSV-1 keratitis was reduced in the DMF group (P < 0.01). In the corneas from DMF-treated mice, the numbers of CD3+ and CD4+ cells were decreased and IL-4 was increased. Severity of epithelial disease and the virus-clearance from the eyes did not differ between the PBS and DMF group of mice. DTH, HSV-specific T cell proliferation and the neutralizing antibody-titres were not impaired. DMF increased the T helper-2-cytokine secretion in activated lymphocytes. After corneal HSV-1 infection, corneas from DMF treated mice had increased IL-4 content. This is associated with an improvement of herpetic stromal keratitis and reduced corneal T cell infiltration. DMF did not impair the systemic antiviral response.
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PMID:Improvement of herpetic stromal keratitis with fumaric acid derivate is associated with systemic induction of T helper 2 cytokines. 1617 74

Pseudomonas aeruginosa keratitis destroys the cornea in susceptible Th1 responder C57BL/6 (B6), but not resistant Th2 responder (BALB/c) mice. To determine whether single Ig IL-1R-related molecule (SIGIRR) played a role in resistance, mRNA and protein expression levels were tested. Both were constitutively expressed in the cornea of the two mouse groups. A disparate mRNA and protein expression pattern was detected in the cornea of BALB/c vs B6 mice after infection. SIGIRR protein decreased significantly in BALB/c over B6 mice at 1 day postinfection. Thus, BALB/c mice were injected with an anti-SIGIRR Ab or IgG control. Anti-SIGIRR Ab over control-treated mice showed increased corneal opacity, stromal damage, and bacterial load. Corneal mRNA levels for IL-1beta, MIP-2, IL-1R1, TLR4, IL-18, and IFN-gamma and protein levels for IL-1beta and MIP-2 also were significantly up-regulated in anti-SIGIRR Ab over control mice, while no changes in polymorphonuclear cell number, IL-4, or IL-10 mRNA expression were detected. To further define the role of SIGIRR, RAW264.7 macrophage-like cells were transiently transfected with SIGIRR and stimulated with heat-killed P. aeruginosa or LPS. SIGIRR transfection significantly decreased mRNA levels for IL-1R1, TLR4, and type 1 immune response-associated cytokines (IL-12, IL-18, and IFN-gamma) as well as proinflammatory cytokines IL-1beta and MIP-2 protein expression. SIGIRR also negatively regulated IL-1 and LPS, but not poly(I:C)-mediated signaling and NF-kappaB activation. These data provide evidence that SIGIRR is critical in resistance to P. aeruginosa corneal infection by down-regulating type 1 immunity, and that it negatively regulates IL-1 and TLR4 signaling.
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PMID:SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling. 1678 52

Interleukin-4 (IL-4) has previously been implicated in a protective response to Staphylococcus aureus corneal infection. Consequently, the specific role of IL-4 during S. aureus corneal infection was investigated using IL-4 gene knockout mice. The eyes of IL-4-/- mice and wild-type mice were challenged topically with S. aureus and examined at 24 h post-infection. Keratitis was examined clinically and histologically. Bacterial and polymorphonuclear leucocytes (PMN) numbers were enumerated and cytokine and chemokine levels determined by enzyme-linked immunosorbent assay. Exogenous IL-4 was administered to both IL-4-/- and wild-type mice and clinical parameters were determined. A lack of IL-4 resulted in a significant increase in clinical scores, pathology, bacterial load and neutrophil numbers. The absence of IL-4 also resulted in an upregulation of interferon (IFN)-gamma and a downregulation of IL-6, IL-10 and the chemokines KC and macrophage inflammatory protein-2. Administration of exogenous IL-4 to IL-4-/- mice was protective but time-dependent. This study highlights the protective role of IL-4 during S. aureus infection and emphasizes the balance between IL-4 and IFN-gamma in achieving bacterial control and maintaining the integrity of the cornea. This information may lead to the development of novel therapeutic strategies potentially improving the prognosis for infection of this unique avascular site.
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PMID:The corneal response to infection with Staphylococcus aureus in the absence of interleukin-4. 1738 70

The transfer factor (TF) was described in 1955 by S. Lawrence. In 1992 Kirkpatrick characterized the specific TF at molecular level. The TF is constituted by a group of numerous molecules, of low molecular weight, from 1.0 to 6.0 kDa. The 5 kDa fraction corresponds to the TF specific to antigens. There are a number of publications about the clinical indications of the TF for diverse diseases, in particular those where the cellular immune response is compromised or in those where there is a deficient regulation of the immune response. In this article we present our clinical and basic experiences, especially regarding the indications, usage and dosage of the TF. Our group demonstrated that the TF increases the expression of IFN-gamma and RANTES, while decreases the expression of osteopontine. Using animal models we have worked with M. tuberculosis, and with a model of glioma with good therapeutic results. In the clinical setting we have worked with herpes zoster, herpes simplex type I, herpetic keratitis, atopic dermatitis, osteosarcoma, tuberculosis, asthma, post-herpetic neuritis, anergic coccidioidomycosis, leishmaniasis, toxoplasmosis, mucocutaneous candidiasis, pediatric infections produced by diverse pathogen germs, sinusitis, pharyngitis, and otits media. All of these diseases were studied through protocols which main goals were to study the therapeutic effects of the TF, and to establish in a systematic way diverse dosage schema and time for treatment to guide the prescription of the TF.
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PMID:Indications, usage, and dosage of the transfer factor. 1829 53

Herpes simplex virus (HSV) infection of the cornea culminates in an immunopathological lesion (stromal keratitis--SK) that impairs vision. This report shows that HSV infection results in IL-23 up-regulation, but if this response fails to occur, as was noted in p19-/- mice, the severity of lesions, their incidence and the level of viral induced angiogenesis were significantly increased compared to wild-type (WT) animals (p<0.05). The higher disease severity in p19-/- mice appeared to be the consequence of an increased IL-12 response that in turn led to the induction of higher numbers of IFN-gamma producing CD4(+)T cells, the principal orchestrators of SK. Our results indicate that the severity of HSV induced immunopathological lesions may be mainly the consequence of IL-12 driven Th1 T cell reactions rather than the action of IL-17 producing cells controlled by IL-23.
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PMID:Enhanced viral immunoinflammatory lesions in mice lacking IL-23 responses. 1832 11

Defensins play an important role in both innate and adaptive immunity due to their antimicrobial, regulatory, and chemotactic effects. Nonetheless, the role of murine beta-defensins (mBD) 3 and 4, the murine homologs of human beta-defensins (hBD) 2 and 3, remains unknown in Pseudomonas aeruginosa keratitis. This study explored their role in corneal infection and potential synergy with mBD2, a defensin associated with better outcome in this disease. Immunostaining and real-time RT-PCR data demonstrated that mBD3 and mBD4 expression was inducible and differentially regulated in the infected cornea of resistant BALB/c vs susceptible C57BL/6 (B6) mice. Knockdown studies using small interfering RNA treatment indicated that mBD3, but not mBD4, is required in ocular defense. Moreover, in vivo studies demonstrated individual and combined effects of mBD2 and mBD3 that modulate bacterial load, polymorphonuclear neutrophil (PMN) infiltration, and production of IFN-gamma, MIP-2, IL-1beta, TNF-alpha, inducible NO synthase (iNOS), TLR2, TLR4, MyD88, and NF-kappaB. Most notably, bacterial load was increased at 5 days postinfection by silencing either mBD2 or mBD3, but it was elevated at both 1 and 5 days postinfection when silencing both defensins. PMN infiltration was increased at 1 day postinfection by silencing both defensins or mBD3, but not mBD2 alone. iNOS expression was elevated by silencing mBD2, but it was reduced after silencing mBD3 or both defensins. Additionally, cell sources of mBD2 (macrophages, PMN and fibroblasts) and mBD3 (PMN) in corneal stroma were identified by dual label immunostaining after infection. Collectively, the data provide evidence that mBD2 and mBD3 together promote resistance against corneal infection.
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PMID:Beta-defensins 2 and 3 together promote resistance to Pseudomonas aeruginosa keratitis. 1993 58

Advances in understanding host innate/adaptive immunity and abrogation of immune privilege in ocular viral and bacterial infections have been accomplished using animal models. In Pseudomonas aeruginosa keratitis, mouse models have shown that IL-12-driven IFN-gamma production in Th1 responder strains such as C57BL/6 contributes to corneal perforation, while IL-18-driven IFN-gamma production is associated with bacterial killing and less disease in Th2 responders (BALB/c). The role of neuropeptides, macrophages, and regulation of neutrophil apoptosis is discussed. The potentially blinding Th1 CD4 T-cell-mediated immunopathology referred to as herpes stromal keratitis (HSK) is characterized by breakdown of the normal barrier to blood and lymph angiogenesis in the cornea, a dramatic increase in mature professional antigen-presenting cells, and a heavy leukocytic infiltrate composed primarily of neutrophils. HSK is more frequent and severe in BALB/c than C57BL/6 mice, and varies in severity with the strain and dose of HSV-1 used to infect the cornea.
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PMID:Reviews for immune privilege in the year 2010: immune privilege and infection. 2066 54


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